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Ventriculitis
Introduction
Ventriculitis is the inflammation of the ependymal lining of the cerebral ventricles secondary to an infectious process.[1] Other terms used to describe ventriculitis are "ependymitis," "ventricular empyema," "pyocephalus," and "pyogenic ventriculitis."[2] This indolent but potentially lethal infection can arise after incomplete or unsuccessful treatment of meningitis. Early diagnosis is essential for determining an appropriate and effective treatment modality. Ventriculitis is of particular concern in patients with temporary external ventricular drains (EVDs) or permanent intraventricular shunts that enable cerebrospinal fluid (CSF) diversion.
Etiology
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Etiology
Ventriculitis may be secondary to the following conditions:
Epidemiology
No specific definition or accepted diagnostic criteria have been established for a ventricular infection. "Ventriculitis," "catheter-related infections," and "positive CSF cultures" each describe a type of infection involving the central nervous system (CNS). "True infection," "contamination," "colonization," and "suspected ventriculostomy-related infection" have unique characteristics specific to their diagnostic identification.[5] The incidence of each of these conditions is difficult to quantify because of their different diagnostic criteria.
Ventriculitis secondary to meningitis, also known as pyogenic ventriculitis, is more common in infants than in adults. Risk factors for the development of this infection are associated with low host immunity, which may occur in the presence of conditions like cancer, HIV, diabetes, and alcohol use disorder, and an increased virulence of the causative organism. Ventriculitis should be considered when meningitis fails to respond to antibiotic therapy or recurs despite treatment.[6] A suggested mechanism for the development of ventriculitis is direct hematogenous spread from the choroid plexus. Chronic infection can lead to septations within the ventricles, resulting in multiloculated hydrocephalus, which is more common with bacterial than viral infections and has a worse clinical prognosis.
Causative organisms include streptococci, gram-negative bacilli, and staphylococci.[7] The incidence of gram-negative bacillary meningitis has increased, most likely reflecting an increase in nosocomial meningitis. This condition represents a clinical challenge due to its indolent course and tendency to recur alongside the evolution of multidrug-resistant organisms.[8][9][10]
The incidence of ventricular catheter-related ventriculitis, which some consider healthcare-associated, ranges from 0% to 45%, depending on the catheter insertion technique and postinsertion management.[11][12][13][14] CSF shunt infection rates range from 4% to 41%, typically between 4% and 17%, while EVD-related ventriculitis ranges from 0% to 22%, and lumbar drain meningitis rates are up to 5%. The exact incidence is hard to determine due to unclear definitions, the severity of the underlying illness, skin flora contamination, and catheter-induced CSF pleocytosis. Most studies are single-center and retrospective, involving few patients. However, a recent multicenter study from the United Kingdom reported EVD infection rates between 3% and 18%, or 4.8 to 12.7 per 1000 EVD days.[15]
Catheter-related ventriculitis with gram-negative organisms, approaching 58% in some studies, is associated with significant morbidity and mortality. Gram-positive cocci that consist of skin flora present as isolates in 50% to 60% of infections and include coagulase-negative Staphylococcus (most common), Corynebacterium, Bacillus, Micrococcus, or Propionibacterium species. The rise in gram-negative pathogens, including Escherichia coli, Klebsiella, Enterobacter, Pseudomonas aeruginosa, and Acinetobacter baumannii, as well as drug-resistant organisms, has been attributed to the use of antibiotic prophylaxis against gram-positive bacteria and prolonged hospitalization.
Streptococcus pneumoniae and gram-negative rods are the most common pathogens in ventriculitis following head trauma. Oral flora bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes, cause infections in patients with skull-base fractures. Gram-negative organisms are present in some studies with persistent CSF leaks, approaching 58% of cases.[16]
Pathophysiology
Ventriculitis, either alone or in the setting of meningitis, is associated with choroid plexitis and an inflammatory response of the ependymal lining of the ventricles. Risk factors for catheter-related ventriculitis may be categorized into 3 groups:
- Patient characteristics and their underlying condition
- Events that break into the integrity of the closed system
- Environmental influences
These risk factors include subarachnoid hemorrhage, neurosurgical operations, concurrent systemic infection, external catheter placement (ie, an EVD passing over a shunt), frequent EVD system manipulation, nonadherence to catheter insertion and maintenance protocols, and extended EVD placement duration.[17][18][19][20] Age, sex, and ethnicity do not appear to increase the risk of developing the condition. However, CSF leaks significantly increase the risk of infection by providing the means for retrograde microorganism migration.
Four mechanisms lead to CSF shunt infections. The most common is colonization during initial surgical placement. Other mechanisms include retrograde bacterial migration from the distal catheter end (eg, bowel perforation), needle insertion through the skin into the reservoir for CSF sampling, and hematogenous seeding. For EVDs, infection typically occurs during placement, though retrograde infection also plays a role. Biofilm formation on devices shields microorganisms from the immune response and antimicrobial therapy.
History and Physical
The symptoms of ventriculitis include sustained fever, meningism signs (such as nuchal rigidity, headache, and photophobia), decreased mental status, seizures, and, in some cases, a moribund state.[21] The onset is more subtle in cases of ventriculitis secondary to catheters, trauma, or neurosurgery. Fever and severe presenting symptoms are also often absent, reflecting the predilection of infection for immunocompromised patients. Patients may have fever unrelated to the infection, such as central fever, drug fever, and chemical meningitis. Erythema or tenderness over the subcutaneous shunt tubing suggests an infection. Patients may present with features of obstructive hydrocephalus, particularly infants with inflammatory aqueduct obstruction.
Evaluation
Investigations for ventriculitis include CSF sampling and radiological imaging. The CSF sample may demonstrate a protein count greater than 50mg/dL. This protein elevation may be related to decreased CSF production, as seen in rabbit models of E coli ventriculitis.[22] The CSF may show a glucose level of less than 25mg/dL, cellular pleocytosis of greater than 10 cells/μL with 50% or more polymorphonuclear neutrophils, and a positive culture or gram stain. Cultures may be negative despite active ventriculitis in about 50% of cases due to antibiotic therapy. Cultures may require several days or weeks of incubation before yielding a positive result, particularly for low-virulence organisms such as Propionibacterium acnes, which requires at least 10 days to grow, though treatment should not be delayed.
The presence of oligoclonal immunoglobulin G or M bands, CSF lactate, procalcitonin, and lysozymes can help make an early diagnosis.[23] An increase in the CSF lactate, procalcitonin, and lysozymes suggests bacterial, not viral, infection.[24] A meta-analysis reported a pooled sensitivity and specificity of 93% and 96%, respectively, for CSF lactate, although this result is reduced when antibiotics are administered before CSF collection.[25]
CSF cultures are the primary test for diagnosing healthcare-associated ventriculitis. However, repeated sampling from EVDs without clinical signs of infection increases infection risk and has low diagnostic predictive value.[26][27][28] Catheter-related ventriculitis is challenging to diagnose based on CSF sampling because the results are often subtle, complicating the determination of whether abnormalities are due to infection, device placement, or postoperative changes following neurosurgery.
Ultrasonography may be performed in neonates using a high-frequency transducer through the anterior fontanelle in the coronal and sagittal planes. Ventriculitis may present with increased ependymal thickness, irregularity, and echogenicity, with echogenic debris within the ventricle. Ependymal irregularity arises from the denudation of segments of ependyma, leading to glial proliferation.
Septa may form in later stages of the disease as the inflammatory exudate organizes, consisting of denuded and detached segments of ependyma, along with compartmentalization, intraventricular cyst formation, and obstructive hydrocephalus. Increased echogenicity may appear in the periventricular region due to subependymal infiltration by lymphocytes, plasma cells, and swollen subependymal astrocytes. Additionally, inflammation of the choroid plexus may exhibit increased echogenicity and irregularity. Ultrasound also detects CSF loculations at the shunt terminus in infected ventriculoperitoneal shunts.
Noncontrast computed tomography (CT) demonstrates nonspecific findings, including dependent hyperdense ventricular debris, hydrocephalus, and periventricular low density, along with features of any underlying abnormalities (eg, meningitis with abnormal pial or dura/arachnoid enhancement). The ependymal lining of the ventricles can enhance homogeneously with contrast. Ependymal denudation may contribute to the breakdown of the blood-brain barrier, leading to this enhancement.
Magnetic resonance imaging reveals similar features as CT, with ventricular debris appearing hyperintense to CSF on T1-weighted images and hypointense on T2-weighted images. This finding is the most commonly observed in ventriculitis, present in up to 94% of cases. Intensely restricted diffusion of intraventricular debris may occur on diffusion-weighted imaging and apparent diffusion coefficient maps, similar to cerebral abscesses, although this finding is inconsistent.[29] Fluid-attenuated inversion recovery images are sensitive to subtle periventricular hyperintense signals, detected in 78% of cases.
Radionuclide brain scintigraphy using technetium Tc 99m is useful for evaluating ventricular conditions, as it can help detect abnormalities in ventricular function and circulation. Ventricular uptake on radionuclide brain scintigraphy using technetium Tc 99m may be present in ventriculitis.
Treatment / Management
Antimicrobial therapy that can achieve effective therapeutic concentrations in the CSF is required. Immunocompromised patients need aggressive treatment. Empirical therapy is initiated, with the agent chosen based on the patient’s age and potential infectious etiology. For catheter-related ventriculitis, the antimicrobial choice is generally comprised of vancomycin and an antipseudomonal β-lactam such as cefepime, ceftazidime, or meropenem.
Specific antibiotics are chosen based on in vitro susceptibility and penetration into the CSF when meningeal inflammation is present. The antibiotic treatment duration usually ranges from 10 to 21 days but depends on the identified organism, the CSF glucose, protein, and cell count, and the presenting clinical symptoms.
Intraventricular antibiotics are an option if ventriculitis is refractory to systemic therapy.[30][31] Commonly used antibiotics include aminoglycosides, colistin, daptomycin, tigecycline, and vancomycin. Vancomycin (5-20 mg/d) and gentamicin (1-8 mg/d) are frequent choices, but local microbial policies can influence the ultimate selection. This regimen achieves higher antibiotic levels in the ventricular CSF compared to intravenous administration.[32][33] Antibiotic dosages have been used empirically, with dose adjustments and intervals based on the ability to achieve adequate CSF concentrations. After the initial dose, subsequent amounts may be determined by calculating the inhibitory quotient (the trough CSF concentration divided by the minimal inhibitory concentration (MIC) of the agent for the isolated bacterial pathogen), which should exceed 10 to 20 for consistent CSF sterilization.(A1)
Removing all components of the infected shunt or EVD, in combination with antimicrobial therapy, is recommended for catheter-related infection. This intervention promotes rapid clearing of the infection, as microorganisms can adhere to prosthetic devices and remain viable despite antimicrobial therapy. The decision of when to reimplant the device depends on the patient's medical condition, the identified microorganism, the severity of the infection, and the CSF findings. More recently, neuroendoscopic lavage of the ventricular system has been advocated for ventriculitis using saline, with or without antibiotics.[34][35](B2)
Differential Diagnosis
Ependymal lining enhancement may be present in primary CNS lymphoma or the subependymal spread of glioblastoma, brain metastases, and germinoma. These conditions may be distinguished from ventriculitis with a thorough clinical investigation and prudent diagnostic testing.
Pertinent Studies and Ongoing Trials
Antibiotics-impregnated (0.054% rifampicin and 0.15% clindamycin) and silver-impregnated ventriculostomy catheters have been developed to reduce infection rates with conflicting results.[36][37] Silver-coated catheters provide an antimicrobial surface that can inhibit the growth of bacteria and biofilm formation over an extended period without systemic side effects. One study demonstrated complete growth inhibition of all microorganisms, with almost complete inhibition of biofilm formation for E coli, S aureus, and C albicans, and over 50% inhibition for Enterococcus, coagulase-negative staphylococci, and P aeruginosa after 72 hours.[38]
A significantly lower infection rate was observed with the silver-coated catheter in a randomized controlled trial (RCT). However, the same finding was not observed in pooled non-RCTs during meta-analysis. An RCT comparing antibiotic-impregnated catheters to untreated catheters found that positive CSF cultures were 7 times less frequent in patients using antibiotic catheters (1.3% versus 9.4%).[39]
The British Antibiotic and Silver-Impregnated Catheters for Ventriculoperitoneal Shunts Multicenter Randomized Controlled Trial (BASICS) involves 1,200 patients across 17 centers, comparing silicone, antibiotic-coated, and silver catheters.[40] This study aims to determine whether impregnated catheters reduce early shunt infections; results are currently pending.
Controversy surrounds the routine exchange of EVDs in reducing infection rates. Some literature indicates that infection rates increase after 4 to 5 days of catheter insertion, supporting the recommendation to remove EVD catheters and insert them at a different site if needed for longer than 5 days. However, other studies have shown no benefit to routine catheter exchange.[41] Holloway's study shows an increasing risk of infection during the first 10 days. Infection becomes unlikely beyond this period, although patients remain at risk.[42] This research has led to the recommendation of removing catheters at the earliest clinical opportunity and routinely exchanging them if obstruction or infection is evident.[43]
Prognosis
If untreated, ventriculitis can lead to poor neurological status, hydrocephalus, and death.[44] Early recognition and treatment are essential for successful clinical outcomes. High-quality studies evaluating the prognosis of this condition are lacking.
Complications
Long-term follow-up is recommended due to the risk of recurrent ventriculitis and hydrocephalus. The ventricles and choroid plexus can serve as reservoirs for infection, even when the lumbar puncture yields sterile cultures.[45]
Deterrence and Patient Education
The literature presents inconclusive evidence regarding the efficacy of antibiotic prophylaxis for patients with ventriculostomies.[46] Periprocedural prophylactic antibiotics are currently recommended for patients undergoing CSF shunt placement or EVD insertion. Studies have compared perioperative antibiotics alone with prolonged antibiotics for the duration that the ventricular catheter is in place. Findings indicate a reduction in the incidence of serious CSF infections. However, the selection of resistant or opportunistic organisms, such as Candida species and methicillin-resistant Staphylococcus aureus (MRSA), can occur. Improved catheter maintenance techniques have also been shown to reduce the development of infections.[47]
Experience and the application of aseptic techniques reduce the risk of catheter-related ventriculitis, underscoring the importance of education. Surgical technique plays a crucial role, as lower infection rates are observed when the catheter is tunneled under the skin, away from the distal skin insertion puncture. Healthcare bundles are increasingly employed to minimize EVD-associated infections and include measures such as education, meticulous device handling, CSF sampling only when clinically necessary, and preoperative prophylactic antibiotic administration, all yielding positive results.
Antibiotic prophylaxis is ineffective in patients with posttraumatic CSF fistula formation.[48] Prophylactic antibiotics for craniotomies help prevent surgical site infections. However, such measures do not prevent meningitis and only predispose the patient to the development of more resistant organisms.[49]
Pearls and Other Issues
A need exists for an agreed-upon set of definitions and increased awareness of ventriculitis to adequately determine the incidence and risk factors in an attempt to reduce infection rates. Recommendations are currently based on expert opinion, as rigorous clinical data are not yet available.
New tests are needed to rapidly and reliably detect the common causes of device-related ventriculitis, including cases involving indolent bacteria like P acnes. Novel diagnostic tools, such as polymerase chain reaction on ribosomal RNA and metagenomic sequencing, are under development for use in identifying the cause of ventriculitis.[50] Nucleic acid amplification tests may help to accomplish this goal.
Care is required when sampling CSF to decrease the risk of introducing infection. CSF sampling should be performed based on only clinical need.
Enhancing Healthcare Team Outcomes
A systematic review highlights the need for a collaborative, interprofessional, and multipronged approach to reduce CNS infections, including ventriculitis. A reduction in infections is possible with persistence and teamwork.[51] Predisposing factors for catheter-related infections are nonadherence to maintenance protocols, frequent catheter manipulation, and catheter irrigation.
Nurses caring for patients with a ventriculostomy must remain vigilant for signs of infection and promptly report any abnormalities to the interprofessional team. The infectious disease nurse and consultant should be involved early during management to assist in selecting the appropriate antibiotics and making recommendations regarding catheter type. The pharmacist should ensure that the selected antibiotics are effective against the isolated organism and safe for the patient, reporting any concerns to the team. The wound care nurse should recommend appropriate cleaning solutions for the ventriculostomy site. Improved management and outcomes depend on the education and collaboration of the entire interprofessional team.
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